S1P1 deletion differentially affects TH17 and Regulatory T cells

Abstract

Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

“…In terms of why Th17 cytokines were uniquely affected in the transferred (preactivated/polarized) CD4 + T cell pool, this also makes sense because transferred T cells (which are preactivated in vitro) exhibit increased capacity for proinflammatory cytokine production compared with endogenous T cells (see Figure 5, C vs. E), possibly rendering these T cells more responsive to BAF312 treatment compared with their endogenous counterparts. Indeed, Th17 cells have been shown to be directly affected by S1P signaling (40), and FTY720 treatment (which prevents lymphocytes from responding to S1P) results in a suppressed Th17 response via downregulation of STAT3 phosphorylation (41). Interestingly, modulation of S1P 1,5 signaling with BAF312 treatment at day 5, but not day 8, after adoptive transfer attenuates cortical pathology.…”

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

“…These long-term effects, according to Eken et al, confer an impact not only on lymphoid sequestration but similarly on non-lymphoid tissue regulatory T cell (T REG ) distribution, and, more importantly, on reducing the memory T REG pool in favor of effector T REG [168]. This could have implications for appropriate T cell zone access in lymph nodes via C-C chemokine receptor type 7 (CCR7) and subsequently their ability to control auto-reactive T cells in vivo [168,169]. These findings warrant further investigation into the precise mechanisms by which enzymes and lipids involved in the generation of S1P and their effects were linked to disease progression and treatment.…”

A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

“…Fingolimod represents an unselective functional antagonist to sphingosine 1-phosphate receptors (S1P R ) resulting in S1P R downregulation upon S1P R engagement [ 8 , 9 ]. The successful application of fingolimod in the treatment of various diseases characterized by a perturbed S1P metabolism suggests the strong therapeutic potential of the S1P-S1P R -axis [ 8 , 10 , 11 , 12 ].…”